Monoclonal antibodies against gonadotropin-releasing hormone receptor
Monoclonal antibodies against gonadotropin releasing hormone (GnRH) receptor induce cellular apoptosis of various cancer cells expressing this surface receptor. The monoclonal antibodies and their humanized forms, or fragments thereof, can serve as anti-cancer agents for the treatment of cancer in humans, and can function as analogs of GnRH to affect regulation of reproductive functions or fertility in humans.
1. A monoclonal antibody (mAb) or fragment thereof that reacts specifically with an epitope present in amino acid residues 1-29 (SEQ ID NO:7) of the extracellular domain of the human GnRH receptor, and
that binds to the GnRH receptor with a dissociation constant (K D ) of less than or equal to 10 −7 M, and
that competes with GnRH for binding to the receptor.
2. A monoclonal antibody (mAb) or fragment of claim 1 , wherein:
a) the CDR1 region of the heavy chain is RYSVH (SEQ ID NO:1); and
b) the CDR2 region of the heavy chain is MIWGGGSTDYNSALKS (SEQ ID NO:2); and
c) the CDR3 region of the heavy chain is GNDGYYSFAY (SEQ ID NO:3); and
d) the CDR1 region of the light chain is KSSQSLLNSRTRKNYLA (SEQ ID NO:4); and
e) the CDR2 region of the light chain is WASTRES (SEQ ID NO:5); and
f) the CDR3 region of light chain is KQSYNLYT (SEQ ID NO:6).
3. The mAb or fragment of claim 1 , which comprises the variable region of GHR-106.
4. The mAb or fragment of claim 1 in humanized form.
5. The fragment of claim 1 which is a F(ab′) 2 , Fab, Fv, or scFv fragment.
6. The antibody or fragment of claim 1 , coupled to a detectable marker and/or a therapeutic agent.
7. A pharmaceutical composition comprising the antibody or fragment of claim 1 and a pharmaceutically acceptable excipient.
8. The pharmaceutical composition of claim 7 further comprising an additional therapeutic agent.
9. A method for controlling ovarian stimulation in a method of assisted reproduction, comprising administering to a subject in need of such treatment an effective amount of the mAb or fragment of claim 1 , or a humanized form or pharmaceutical composition thereof.
10. The method of claim 9 , wherein the method of assisted reproduction is In vitro Fertilization (IVF).
11. The mAb or fragment of claim 3 in humanized form.
12. The fragment of claim 3 which is a F(ab′) 2 , Fab, Fv, or scFv fragment.
13. The antibody or fragment of claim 3 , coupled to a detectable marker and/or a therapeutic agent.
14. A pharmaceutical composition comprising the antibody or fragment of claim 3 and a pharmaceutically acceptable excipient.
15. The pharmaceutical composition of claim 14 further comprising an additional therapeutic agent.
16. A method for controlling ovarian stimulation in a method of assisted reproduction, comprising administering to a subject in need of such treatment an effective amount of the mAb or fragment of claim 3 , or a humanized form or pharmaceutical composition thereof.
17. The method of claim 16 , wherein the method of assisted reproduction is In vitro Fertilization (IVF).